Estrogenic compounds and animal growth promoters



United States Patent 3,373,036 ESTROGENIC COMPOUNDS AND ANIMAL GROWTH PROMOTERS Edward B. Hodge, Phil H. Hidy, and Herbert L. Wehrmeister, Terre Haute, Ind., assignors to Commercial Solvents Corporation, a corporation of Maryland N0 Drawing. Continuation-impart of application Ser. No. 561,410, June 29, 1966. This application Mar. 3, 1967, Ser. No. 620,286.

Claims. (Cl. 99-2) ABSTRACT OF THE DISCLOSURE R-O (l) CH3 (JOCH(CH2)3 Where R is selected from the group consisting of hydrogen, benzyl and lower alkyl, A is a radical selected from the group consisting of CH=CH-- and -OH CH and B is a radical selected from the group consisting of --CH CG and -CO-CH and animal feeds containing growth promoting amounts thereof.

This application is a continuation-in-part of application Ser. No. 561,410, filed June 29, 1966 now abandoned.

The present invention relates to new compounds and an object of the present invention is to provide compounds which exhibit estrogenic activity of aid in increasing the rate of growth in meat-producing animals, e.g., cattle, lamb and swine.

The compounds of this invention are illustrated by the formula:

B R-O- \A 2)s wnere A is -CH CH or CH=CH-; R is hydrogen, substituted or unsubstituted alkyl, e.g., lower alkyl such as methyl, ethyl, hexyl, etc. or aralkyl, e.g., benzyl; and B is -CH -CO or COCH The compounds of the present invention can be produced from the compound:

hereinafter referred to as the fermentation estrogenic substance (F.E.S.) by enlargement through reaction with diazomethane. The hydroxyl groups should be protected against undesirable side reactions before ring enlargement which can be accomplished by converting them to ethers, e.g., methyl ethers as taught in US. Patent 3,239,342 or benzyl ethers as taught in application Ser. No. 532,113, filed Mar. 7, 1966 now abandoned, and application Ser. No. 620,259, filed Mar. 3, 1967, and subsequently removing the masking group to regenerate the hydroxyl group. The hydroxyl group can be regenerated from, for example, a methyl ether by hydrolysis or by refluxing in acetic acid solution with hydrobromic acid. Benzyl groups are removed by reduction. Aluminum chloride is another effective dealkylating agent.

The compounds can be administered to animals by any suitable method including oral and parenteral administrations. For example, the compound can be blended with ordinary feed containing nutritional values in an amount sufiicient to produce the desired rate of growth and can thus be fed directly to the animals, or the compound can be suspended in a suitable injection suspension 1nedium such as peanut oil and injected parenterally. The amount of compound fed to an animal, of course, varies depending upon the animal, desired rate of growth and the like.

When the new compounds are to be administered in feeds, an animal feed composition may be prepared containing the usual nutritionally-balanced quantities of carbohydrates, proteins, vitamins and minerals, together with the compound of the present invention. Some of these usual dietary elements are grains, such as ground grain and grain by-products; animal protein substances, such as those found in fish meal and meat scraps, vegetable proteins like soybean oil meal or peanut oil meal; vitaminaceous materials, e.g., vitamin A and D mixtures; riboflavin supplements and other vitamin B complex members; and bone meal and limestone to provide minerals. A type of conventional feed material for use with cattle includes alfalfa hay and ground corn cobs together with supplementary vitaminaceous substances if desired.

The following examples serve to further illustrate the invention.

Example I F.E.S. 2,4-dimethylether is mixed with excess diazomethane in dry ether at 0 C. and methanol is slowly added whereupon nitrogen is released. After the reaction subsides, the mixture is allowed to stand at room temperature for about 3 days and then filtered. The products are:

CHOa

CHOa

I 0 CH3 Example II Compound (1) is demethylated by heating at 120 C. in benzene with two equivalents of aluminum chloride to produce:

Example III Six head of cattle are fed a daily ration of alfalfa, hay and ground corn cobs containing from 5 to 20 ounces per pounds of feed of compound 1 of Example I and their rate of growth is improved.

3 Example V Six head of cattle are fed a daily ration of alfalfa hay and ground corn cobs containing from 5 to 20 ounces per 100 pounds of feed of the compound produced in Example 11 to improve their rate of growth.

The following are specific examples of animal feed compositions of this invention useful for increasing the rate of growth and feed efficiency of young animals to market weight.

Example VI For young beef cattle, i.e., calves to yearlings running to two years 01 65, each animal is given 5 to 20 milligrams per day of the compound produced in Example I intimately admixed in about l8 to 22 pounds per head per day of a complete pelleted ration for about 180 days. The complete pelleted ration includes in addition to the compound of Example I the following:

Barley percent 40-43 Molasses dried beet pulp do 34.5-37.5 Alfalfa pellets 'd-o 8.0 Tallow do .30 Calcium carbonate do .30 Urea do .30 Phosphorus source do .40 Salt =do- .50 Molasses do 10.00 Trace mineral do 0.5 Vitamin A MM'I.U/ton 2-4 Note.-Milo or corn, for example, can be substituted for the barley.

The compound of Example I is admixed with the above ingredients in a stationary blender or a feed mix truck in the following amounts in grams per ton to provide an appropriate complete pelleted feed with dosage levels ranging from 5 to 90' milligrams per head per day.

Grams/ton: Mg./head/day 5 5 10 10 20 20 40 4O 8 80 These gram amounts :are premixed with, for example, 10 pounds of soybean hulls prior to admixture with the other ingredients.

Example VII For young swine, i.e., six-week-old pigs to about 100- pound pigs, each animal is given to 20 milligrams per day of the compound of Example II intimately admixed in about l /2 to 5 /2 pounds per head per day of :a grower ration until it reaches a weight of about 100 pounds. When the swine weigh between 90 and 125 pounds the feed is changed to one whereby each animal is given 20 to 50 milligrams per day of the compound of Example II intimately admixed in about 5 /2 to pounds per head per day of a finisher ration until it reaches market weight of about 220 pounds. The grower and finisher ration include in addition to the compound of Example II the following:

The compound of Example II is admixed with the above ingredients in a blender in the following amounts in milligrams per pound to provide an appropriate feed with dosage levels ranging from 6 to 96 milligrams per head per day.

Mg./pound Mg/head/day 2 6 4 12 8 24 16 48 32 96 Examples VIII For 4- to lO-months old lambs weighing 50 to 70 pounds, each animal is given -1 to 15 milligrams per day of the compound of Example I, intimately admixed in about 3 to 6 pounds per head per day of a complete ration for 30 to days. The complete ration includes in addition to the compound of Example I the following:

Pounds Finely ground corn cobs 630 Ground corn 600 Dehydrated alfalfa meal 300 Dried molasses Soybean meal (44% protein) 300 Dicalcium phosphate 14 Trace mineral salt 17 Premix vitamin, mineral and antibiotic 19 The compound of Example I is admixed with the above ingredients in a blender in the following amounts in milligrams per pound to provide an appropriate complete feed with dosage levels ranging from '1 to 15 milligrams per head per day.

Mg./ pound Mg./ head/ day .5 2 1.0 4 1.5 6 2.0 8 2.5 10 3.75 15 Example IX For broilers, i.e., day-old to four-week-old chicks, a grower feed is prepared for feeding to the chicks for the first four weeks and a finisher feed is prepared for feeding the four week old chicks for the last five weeks until they reach market weight of two and a half to three pounds dressed. For each pound of weight gain, the chicks eat about 1.5 to 2 pounds of feed. Thus they eat about 1.5 pounds of feed during the first four weeks and about fi=ve pounds of feed during the next five weeks. During the course of this feeding schedule, each bird should receive a total of about 12 to 36 milligrams of the compound of Example II in the grower and finisher feed each of which includes in addition to the compound of Example II the following:

It is claimed:

6 where -R is selected from the group consisting of 6. The compound of claim 2 whereinA is hydnogen, benzyl and lower 'alkyl, A is a radical selected from the group consisting of 2 P and B is -CO-CH e-. CH=CH- and -CH -CH 7. The compound of claim 1 wherein. R is hydrogen. 8. The compound of claim 1 wherein R is benzyl.

a? f gi gg g f i the group conslstmg of An animal feed composition comprising a nutrient 2 The compound of ciaim 1 wherein R is lower alkyl. when. and growth Promotmg amount of the compound 3. The compound of l i 2 wherein A is C aim 1.

I 10. An animal feed composition comprising a nutrient -E Eg $;L i gg ggz wherein A is 10 ration and growth promoting amount of the compound i of claim 3. CH=CH- and B 18 CO-CH 5. The compound of claim 2 wherein A is NO refemnces 15 A. LOUIS MONACELL, Primary Examiner.

. K A I i t andBis CHZ CO' H H L RE III Asszs ant Exwmzner UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,373,036 May 12, 1968 Edward B. Hodge et a1.

It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Column 1, line 33, "of" should read or line 45, "wnere" should read where Column 2, lines 38 to 42, and lines 44 to 49, the left-hand portion of the formula, each occurrence, should appear as shown below:

H CO

Column 3, line 2, after "alfalfa" insert a comma; line 22, should read 2 5 Column 5 line 7 "CH -CO and COC should read --CH CO- and -CO-CHZ-- line 17, "and B is-CH CO." should read and B is -CH CO.

Signed and sealed this 21st day of October 1969.

(SEAL) Attest:

EDWARD M.FLETCHER,JR. WILLIAM E. SCHUYLER, JR. Attesting Officer Commissioner of Patents 

